The connection between abnormal protein phosphorylation and the cause or consequence of diseases has been known for over 20 years. Accordingly, protein kinases have become a very important group of drug targets. [See Cohen, Nature, 1:309-315 (2002), Gaestel et al. Curr. Med. Chem. 14: 2214-223 (2007); Grimminger et al. Nat. Rev. Drug Disc. 9(12):956-970 (2010)]. Various protein kinase inhibitors have been used clinically in the treatment of a wide variety of diseases, such as cancer and chronic inflammatory diseases, including rheumatoid arthritis and psoriasis. [See Cohen, Eur. J. Biochem., 268:5001-5010 (2001); Protein Kinase Inhibitors for the Treatment of Disease: The Promise and the Problems, Handbook of Experimental Pharmacology, Springer Berlin Heidelberg, 167 (2005)].
The elucidation of the intricacy of protein kinase pathways and the complexity of the relationship and interaction among and between the various protein kinases and kinase pathways highlights the importance of developing pharmaceutical agents capable of acting as protein kinase modulators, regulators or inhibitors that have beneficial activity on multiple kinases or multiple kinase pathways. Accordingly, there remains a need for new kinase modulators.
The protein kinase C (PKC) family is a group of serine/threonine kinases that is encompasses twelve related isoenzymes. The PKCs are expressed in a wide range of tissues and cell types. The PKC isozymes can be classified into three groups. Group I (classical PKCs) includes the Ca2+ and DAG (diacylglycerol) dependent isozymes: PKC-α, PKC-βI, PKC-βII and PKC-γ. Group II (novel PKCs) includes the Ca2+ independent isozymes: PKC-δ (or PKC-delta), PKC-ε, PKC-η (or PKC-eta) and PKC-θ (or PKC-theta). Group III (atypical PKCs) includes the Ca2+ and DAG independent isozymes: PKC-ι, PKC-ζ and PKC-μ (protein kinase D). The PKC-theta isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, and the subsequent release of cytokines such as IL-2 and T cell proliferation (Isakov and Altman, Annu Rev. Immunol., 2002, 20, 761-94). It has been well established that T cells play an important role in regulating the immune response (Powrie and Coffman, Immunology Today, 1993, 14, 270) and the activation of T cells is often the initiating event in a variety of immunological disorders. Upon activation via the TCR, T cells produce cytokines, including IL-2, leading to cell proliferation, differentiation, and effector function. Clinical studies with inhibitors of IL-2 have shown that interference with T cell activation and proliferation effectively suppresses immune response in vivo (Waldmann, Immunology Today, 1993, 14, 264). Accordingly, agents that inhibit T lymphocyte activation and subsequent cytokine production are therapeutically useful for selectively suppressing the immune response in a patient in need of such immunosuppression and therefore are useful in treating immunological disorders such as autoimmune and inflammatory diseases. PKC-theta activation has also been implicated in leukemia and thus inhibitors of PKC-theta may be useful for the treatment of leukemia (Villalba and Altman, Current Cancer Targets, 2002, 2, 125).
PKC-delta is closely related to PKC-theta, however, they exhibit different tissue expression patterns and serve unique cell functions. While PKC-theta is highly expressed in T-lymphocytes, NK cells and to a lesser extent in skeletal muscle, PKC-delta is highly expressed in myeloid cells and B-lymphocytes (ExPasy database; PRKCT and PRKCD). PKC-delta is important for the regulation of B-cell tolerance so that mice lacking PKC-delta exhibit increased numbers of self-reactive B-cells, elevated IL-6, express auto-antibodies to nuclear antigens, and exhibit a lupus-like pathology (Mecklenbrauker et al., Nature, 2002, 416, 860-865; Miyamoto et al., Nature, 2002, 416, 865-869). Furthermore, genetic examination of siblings with juvenile onset lupus identified a mutation in the PKC-delta (PRCKD) gene (Belot et al., Arthritis&Rheumatism, 2013, 65, 2161-2165). For this reason, inhibition of PKC-delta may be detrimental in the treatment of autoimmune disease and there is rationale for avoiding chronic inhibition of this enzyme. Selective inhibition of PKC-delta for therapy has previously been clinically evaluated (delcasertib; Kai Pharmaceuticals) in the context of acute treatment of ischemia-reperfusion injury.
There remains a need to develop effective therapeutic agents for the majority of the diseases and disorders associated with activation of PKC-theta (Chaudhary and Kasaian, Curr Opin Investig Drugs 2006 7(5):432-437; Zhang, E. Y, Kong, K., and Altman, A., Adv Pharmacol 2013, Vol 66, 267-312; Chand, S., et. Al. Curr Pharmaceut Design 212, Vol 18(30):4725-4746). Accordingly, it would be beneficial to provide safe and effective compounds that are useful as selective inhibitors of PKC-theta and thus in the treatment of disorders and diseases associated with activation of PKC-theta. In particular there remains a need for effective therapeutic agents that are selective inhibitors of PKC-theta, without affecting other members of the PKC family, such as PKC-delta and/or PKC-eta.
Citation or identification of any reference in Section 2 of this application is not to be construed as an admission that the reference is prior art to the present application.